Targeted inhibition of physiologic and pathologic processes

ABSTRACT

In some embodiments, sympathetic nerves surrounding arteries or leading to organs are targeted with energy sources to correct or modulate physiologic processes. In some embodiments, different types of energy sources are utilized singly or combined with one another. In some embodiments, bioactive agents or devices activated by the energy sources are delivered to the region of interest and the energy is enhanced by such agents.

PRIORITY DATA

This application is a continuation of U.S. patent application Ser. No.12/685,655, filed on Jan. 11, 2010, pending, which claims priority to,and the benefit of U.S. Provisional Patent Application No. 61/256,983filed Oct. 31, 2009, now lapsed, U.S. Provisional Patent Application No.61/250,857 filed Oct. 12, 2009, now lapsed, U.S. Provisional PatentApplication No. 61/261,741 filed Nov. 16, 2009, now lapsed, and U.S.Provisional Patent Application No. 61/291,359 filed Dec. 30, 2009, nowlapsed, the entire disclosures of all of which are expresslyincorporated by reference herein.

BACKGROUND

Energy delivery from a distance involves transmission of energy waves toaffect a target some distance a way. It allows for more efficientdelivery of energy to targets and greater cost efficiency andtechnologic flexibility on the generating side. For example, cellularphones receive targets from towers close to the user and the towerscommunicate with one another over a long range; this way, the cellphones can be low powered and communicate over a relatively small rangeyet the network can quickly communicate across the world. Similarly,electricity distribution from large generation stations to the users ismore efficient than the users themselves looking for solutions.

In terms of treating a patient, delivering energy over a distanceaffords great advantages as far as targeting accuracy, technologicflexibility, and importantly, limited invasiveness into the patient. Ina simple form, laparoscopic surgery has replaced much of the previousopen surgical procedures and lead to creation of new procedures anddevices as well as a more efficient procedural flow for diseasetreatment. Laparoscopic tools deliver the surgeon's energy to thetissues of the patient from a distance and results in improved imagingof the region being treated as well as the ability for many surgeons tovisualize the region at the same time. Perhaps most important is thefact that patients have much less pain, fewer complications, and theoverall costs of the procedures are lower.

Continued advances in computing, miniaturization and economization ofenergy delivery technologies, and improved imaging will lead to stillgreater opportunities to apply energy from a distance into the patientand treat disease.

SUMMARY OF INVENTION

What is described herein are procedures and devices which advance theart of medical procedures involving transmitted energy to treat disease.That is, the procedures and devices described below follow along thelines of: 1) transmitting energy to produce an effect in a patient froma distance; 2) allowing for improved imaging or targeting at the site oftreatment; 3) creating efficiencies through utilization of larger andmore powerful devices from a position of distance from the patient asopposed to attempting to be directly in contact with the target.

In some embodiments, an imaging system is provided, as is a therapeuticdelivery system.

In some embodiments, regions of the eye other than the retina aretargeted with ablative or sub-ablative energy from outside the eye.

In some embodiments, the ciliary muscles are targeted and in someembodiments, the zonules surrounding the lens are targeted. In certainembodiments related to the eye, presbyopia is treated and in certainembodiments, elevated intraocular pressure is treated.

In some embodiments, the macula is targeted with non-ablative focusedenergy. Non-ablative focused or unfocused energy can be utilized toassist in the transcleral or intravitreal release of bioactive agentsinto the eye.

In some embodiments, non-focal, non-ablative energy is applied to thesclera to assist in the transcleral migration of bioactive materials tothe choroidal space below the retina.

In some embodiments, ducts such as the fallopian tubes or the vasdeferens are targeted for permanent or semi-permanent sterilizationusing ablative energy.

In some embodiments, vascular structures such as the saphenous vein,femoral vein, and iliac veins are directly targeted to treat venousdiseases such as occlusions or faulty venous valves.

In some embodiments, intra-vascular clots, devices, or other vascularabnormalities such as aneurysms or arterial-venous malformations, aretargeted.

In some embodiments, sympathetic nerves surrounding arteries aretargeted for ablation or sub-ablative interruption. In some embodiments,the renal nerves which surround the pedicles of the kidneys aretargeted. In some embodiments, circles or elliptical rings are createdaround the renal arteries and in some embodiments, the circles or ringsare created closer to the bifurcation of the renal arteries as theyreach the kidneys. In other embodiments, nerves running down the aortaare targeted as they branch off to the renal arteries.

In some embodiments, whole or partial sympathetic ganglia positionedclose to blood vessels are targeted. In some embodiments, ganglia alongthe sympathetic chain along the spine are targeted as entire structuresto target and alter physiologic processes. In other embodiments, thedorsal roots of the spinal cord are targeted with energy to partially orfully ablate the renal afferent nerves traveling through them.

In some embodiments, nerves to joints are targeted with ablative ornon-ablative energy such as for example, the spine, the knee, or thehip.

In some embodiments, vessels are detected and placed in a coordinateframe to be treated with the focused energy system but regions (forexample, nerves) just outside the vessels are treated. For example, thecarotid artery, superior mesenteric artery, aorta, vena cava, renalveins, iliac arteries, ophthalmic artery, and ciliary arteries are allarteries which are potential targets for interruption of surroundingnerves. The vessels, however, are the targets localized by the externalimaging and energy delivery systems.

In some embodiments, a device and method to interrupt nerve fibers, atleast partially, from a position external to a patient is described. Theembodiment involves the application of energy from a region external tothe patient to the region of the nerve fibers. In some embodiments,energy is delivered from multiple directions and meet at the region ofthe nerve so as to deliver the effect.

In some embodiments, an external energy source delivers energy from twodifference positions to focus energy on a region of interest (forexample, the sympathetic nerve regions of the renal arteries).

In another embodiment, image detectors are embedded in the devicesdelivering the energy so that the imaging of the region of interest isalso determined from two different angles to determine the location ofthe target in three dimensions.

In another embodiment, range finders (e.g. acoustic or sonar) are usedto detect distances or positions of structures.

In some embodiments, a renal artery is detected using doppler ultrasoundtechnology. By detecting the position of the renal arteries from morethan one angle via doppler triangulation, a three dimensional map can becreated and the renal artery can be mapped into a coordinate referenceframe. A pattern of energy can be applied to the renal artery based onthe knowledge of the coordinate reference frame. Once the renal arteryis placed in the coordinate frame, an algorithm is utilized to localizethe delivery of focused ultrasound to heat the adventitia of the arterywhich contains the sympathetic nerves to the kidney and therebydecreasing the sympathetic stimulus to the kidney to potentially controlhypertension.

In other embodiments, vessels are detected and placed in a coordinateframe to be treated with the focused energy system. For example, thecarotid artery, superior mesenteric artery, aorta, vena cava, renalveins, iliac arteries, ophthalmic artery, and ciliary arteries are allarteries which are potential targets of sympathetic nerve interruption.In some embodiments, the techniques described can be applied to anyother blood vessel adventitia or nerve plexus surrounding any bloodvessel in the body.

In some embodiments, the location of the stomach is utilized because ofits position overlying the celiac plexus and position partiallyoverlying the abdominal aorta. In this embodiment, a nasogastric tube isplaced inside the stomach and can be utilized to stimulate or inhibitthe celiac axis through the stomach wall using focused or non-focusedenergy sources.

In some embodiments, the celiac axis or associated nerves can also bedirectly ablated using energy based transducers through the stomach orthrough the aorta or from an external position.

In another embodiment, ionizing radiation is used and generated fromequipment such as a megavoltage linear accelerator, proton beamaccelerator, or orthovoltage X-ray generator.

In some embodiments, CT scan imaging or other imaging systems (forexample, ultrasound), such as MRI can be used to target the regionaround the renal arteries where the sympathetic nerves sit.

In some embodiments, the ionizing radiation sources may also be coupledto CT or MRI scanners which can further aid in the identification of theregion of the sympathetic nerve plexus.

In some embodiments, the ultrasound transducers are placed externallyand the renal arteries are located in more than one axis using a dopplersignal detected from the renal artery blood flow.

In some embodiments, an arrangement of the ultrasound transducers issuch that each transducer has the ability to be moved relative to oneanother and with respect to the target (e.g. renal blood vessels).

Such movement allows for adjustment of focal distance and position inthe X-Y plan which may change with position.

In some embodiments, a kidney and a renal artery, or just a kidney, istargeted with the ultrasound transducers.

In some embodiments, ultrasound transducers are used to detect Dopplerblood flow and simulate the position of the heating spot at the focalregion of the transducers.

In some embodiments, a three dimensional view of the renal arteries andrenal pedicle is obtained using the ultrasonic images so that the heatedregion is simulated in three dimensions so as to avoid the criticalstructures around the renal pedicle such as the renal vein, adrenalartery, and the adrenal gland itself.

In some embodiments, a three-dimensional image of a renal artery enablesprecise placement of the heat generating spot because there are nervesproximal to the generated spot. In some embodiments, coupling of therenal artery doppler signal using two separate detectors allows thethree dimensional coordinates of the renal artery to be determined inreal space. In some embodiments, once the renal artery position isdetermined in real space, the 3D location of the heating via thetherapeutic ultrasound transducers can be determined, in theory, quitequickly. Heating damage to organs surrounding the renal arteries canalso be determined, modeled, and minimized.

In some embodiments, a puncture in the skin may be needed so as to takeadvantage of additional refinements in technology or to treat patients(e.g. obese patients) who are not amenable to completely externaltherapy. In this embodiment, the puncture in the skin may enable acatheter to be passed into an artery or vein and to the renal artery orvein. In some embodiments, a catheter is placed percutaneously, directlyto the nerve region surrounding the vessels; that is, nottransvascularly.

In other embodiments, catheters may be placed through the subcutaneoustissues and into the space around the renal artery or vein. In either ofthese embodiments, the sympathetic nerves can be ablated or the nerveconduction pathways can otherwise be interrupted to result in a decreasein neurotransmitter release from the sympathetic terminals at the levelof the kidney.

In addition to, or in place of, the renal sympathetic nerves, in someembodiments, it may be desirable to ablate or partially inhibit nerveswhich relate to the carotid or aortic baroreceptors. For example,cardiac afferent nerves have been known to dampen the carotid bodyresponse when activated which results in a loss of the parasympatheticresponse to elevated blood pressure. In such a scenario, the cardiacafferent nerves can be ablated so that the baroreceptor response remainssensitive to increased blood pressure and can stimulate theparasympathetic system to decrease adrenergic drive in the face ofelevated blood pressure.

In some embodiments, the sympathetic or parasympathetic nerves leadingto the eye are ablated, stimulated, partially ablated, or partiallystimulated so as to control intraocular hypertension or otherphysiologic processes. These sympathetic nerves are well known as beingcausative for increases in intraocular pressure. Indeed, a best sellingpharmaceutical, tenoptic, acts against the adrenergic response in theeye and so ablating the sympathetic nerves would offer a more permanentfix to the elevated intraocular blood pressure.

In one embodiment, the ultrasound transducers used for ablation alsocontain at least one imaging transducer. The imaging transducer can beutilized for quick imaging and registration with the MRI or thetransducer can be utilized for detection of fiducials within thetreatment region. Such fiducials can be placed in the field or may benaturally present. In one embodiment, an intravascular catheter isplaced with a recognizable beacon to indicate the position of thecatheter, artery, and hence the nerves surrounding the artery.

In another embodiment, radiation is applied to the region outside theartery to prevent re-growth of the sympathetic nerves after ablation.

In another embodiment, ablative energy is applied to a region of afallopian tube to close the tube and prevent ovulation and transfer ofovum to a uterus.

In one embodiment, a method of inhibiting the function of a nervetraveling with an artery comprises; providing an external imagingmodality to determine the location of the artery through the skin of apatient; placing the artery in a three dimensional coordinate referencebased on the imaging; placing a therapeutic energy generation source ina three dimensional coordinate reference frame; coupling the threedimensional coordinate frame of the energy source and the artery;modeling the delivery of energy to the adventitial region of the arteryor a region adjacent to the artery where a nerve travels; deliveringtherapeutic energy from the therapeutic energy source, from at least twodifferent angles, through the skin of a patient, to intersect at anartery or the region adjacent to the artery to at least partiallyinhibit the function of a nerve.

In some embodiments, the imaging source is one of: ultrasound, MRI, andCT.

In some embodiments, the therapeutic energy is ultrasound.

In some embodiments, the artery is a renal artery.

In some embodiments the involve placing the artery in a threedimensional reference frame involving locating the artery using adoppler ultrasound signal.

In some embodiments, the fiducial is placed internal to the patient.

In some embodiments, the fiducial is temporarily placed in a positioninternal to the patient.

In some embodiments the fiducial is a catheter placed in the artery ofthe patient.

In some embodiments the catheter is detectable using an acoustic signaland said imaging modality is ultrasound.

In some embodiments, the method involves therapeutic energy from theenergy source which is delivered in a distribution along the length ofthe artery.

In some embodiments the therapeutic energy is ionizing radiation.

In some embodiments, a system to inhibit the function of a nervetraveling with a renal artery comprises a detector to determine thelocation of the renal artery and renal nerve through the skin of apatient; an ultrasound component to deliver therapeutic energy throughthe skin from at least two directions to the nerve surrounding the renalartery; a modeling algorithm comprising an input and an output saidinput to the modeling algorithm comprising a three dimensionalcoordinate space containing a therapeutic energy source and the positionof the renal artery; and, the output from the modeling algorithmcomprises: the direction and energy level of the ultrasound component; alocatable fiducial, adapted to be temporarily placed in the artery of apatient and communicate with the detector to determine the location ofthe renal artery in a three dimensional reference, the informationregarding the location transmittable as the input to the model.

In some embodiments, the fiducial is a passive reflector of ultrasound.

In some embodiments, the system fiducial generates radiofrequencyenergy.

In some embodiments, the system fiducial is activated to transmit energybased on a signal from an ultrasound generator.

In some embodiments, the system output from the model instructs theultrasound component to deliver a lesion on the artery in which themajor axis of the lesion is longitudinal along the length of the artery.

In some embodiments, the system output from the model instructs theultrasound component to deliver multiple lesions around an arterysimultaneously.

In some embodiments, the system output from the model instructs theultrasound component to deliver a circumferential lesion around theartery.

In some embodiments, a lesion is placed around the renal artery justproximal to the bifurcation of the artery in the hilum of the kidney.

DESCRIPTION OF FIGURES

FIGS. 1 a-b depict the focusing of energy sources on nerves of theautonomic nervous system.

FIG. 1 c depicts an imaging system.

FIG. 2 depicts targeting and/or therapeutic ultrasound delivered throughthe stomach to the autonomic nervous system posterior to the stomach.

FIG. 3 a depicts focusing of energy waves on the renal nerves FIG. 3 bdepicts a coordinate reference frame.

FIG. 4 depicts the application of energy to the autonomic nervous systemsurrounding the carotid arteries

FIGS. 5 a-b depict the application of focused energy to the autonomicnervous system of the eye.

FIG. 6 depict the application of lesions to the kidney deep inside thecalyces.

FIG. 7 a depicts a patient in an imaging system receiving treating withfocused energy waves.

FIG. 7 b depicts visualization of a kidney being treated.

FIG. 7 c depicts a close up view of the renal nerve region of the kidneybeing treated.

FIG. 7 d depicts a method to treat the autonomic nervous system usingMRI and energy transducers.

FIG. 8 a depicts a percutaneous approach to treating the autonomicnervous system surrounding the kidneys.

FIG. 8 b depicts an intravascular approach to treating the autonomicnervous system.

FIGS. 9 a-c depicts the application of energy from inside the aorta toregions outside the aorta.

FIG. 10 depicts steps to treat a disease using HIFU.

FIG. 11 a depicts treatment of brain lesions using cross sectionalimaging.

FIG. 11 b depicts an image on a viewer showing therapy of the region ofthe brain being treated.

FIG. 11 c depicts another view of a brain lesion.

FIG. 12 depicts treatment of the renal nerve region using a laparoscopicapproach.

FIG. 13 depicts a methodology for destroying a region of tissue usingimaging markers.

FIG. 14 depicts the partial treatment of a nerve bundle using convergingimaging waves.

FIG. 15 depicts the application of focused energy to the vertebralcolumn.

FIG. 16 depicts the types of lesions which are created around the renalarteries to affect a response.

FIGS. 17 a depicts the application of multiple transducers to treatregions of the autonomic nervous system.

FIGS. 17 b-c depict methods and devices to treat a specific regionsurrounding an artery.

FIG. 17 d depicts a method for localizing HIFU transducers relative toDoppler ultrasound signals.

FIG. 17 e depicts an arrangement of transducers relative to a target.

FIG. 17 f depicts ablation zones in a multi-focal region incross-section.

FIG. 18 depicts the application of energy internally within the kidney.

FIG. 19 depicts the direction of energy wave propagation to treatregions of the autonomic nervous system around the kidney region.

FIG. 20 depicts the application of ultrasound waves through the wall ofthe aorta

FIG. 21 a depicts application of focused energy to the ciliary musclesand processes of the eye.

FIG. 21 b depicts the application of focused non-ablative energy to theback of the eye to enhance drug or gene delivery or another therapy suchas ionizing radiation.

FIG. 22 depicts the application of focused energy to nerves surroundingthe knee joint.

FIGS. 231-23 b depict the application of energy to the fallopian tube tosterilize a patient.

FIG. 24 depicts an algorithm to assess the effect of the neuralmodulation procedure on the autonomic nervous system. After a procedureis performed on the renal nerves, assessment of the autonomic responseis performed by, for example, simulating the autonomic nervous system inone or more places.

DETAILED DESCRIPTION OF THE INVENTION

Congestive Heart Failure (“CHF”) is a condition which occurs when theheart becomes damaged and blood flow is reduced to the organs of thebody. If blood flow decreases sufficiently, kidney function becomesaltered, which results in fluid retention, abnormal hormone secretionsand increased constriction of blood vessels. These results increase theworkload of the heart and further decrease the capacity of the heart topump blood through the kidneys and circulatory system.

It is believed that progressively decreasing perfusion of the kidneys isa principal non-cardiac cause perpetuating the downward spiral of CHF.For example, as the heart struggles to pump blood, the cardiac output ismaintained or decreased and the kidneys conserve fluid and electrolytesto maintain the stroke volume of the heart. The resulting increase inpressure further overloads the cardiac muscle such that the cardiacmuscle has to work harder to pump against a higher pressure. The alreadydamaged cardiac muscle is then further stressed and damaged by theincreased pressure. Moreover, the fluid overload and associated clinicalsymptoms resulting from these physiologic changes result in additionalhospital admissions, poor quality of life, and additional costs to thehealth care system. In addition to exacerbating heart failure, kidneyfailure can lead to a downward spiral and further worsening kidneyfunction. For example, in the forward flow heart failure describedabove, (systolic heart failure) the kidney becomes ischemic. In backwardheart failure (diastolic heart failure), the kidneys become congestedvis-à-vis renal vein hypertension. Therefore, the kidney can contributeto its own worsening failure.

The functions of the kidneys can be summarized under three broadcategories: filtering blood and excreting waste products generated bythe body's metabolism; regulating salt, water, electrolyte and acid-basebalance; and secreting hormones to maintain vital organ blood flow.Without properly functioning kidneys, a patient will suffer waterretention, reduced urine flow and an accumulation of waste toxins in theblood and body. These conditions result from reduced renal function orrenal failure (kidney failure) and are believed to increase the workloadof the heart. In a CHF patient, renal failure will cause the heart tofurther deteriorate as fluids are retained and blood toxins accumulatedue to the poorly functioning kidneys. The resulting hypertension alsohas dramatic influence on the progression of cerebrovascular disease andstroke.

The autonomic nervous system is a network of nerves which affect almostevery organ and physiologic system to a variable degree. Generally, thesystem is composed of sympathetic and parasympathetic nerves. Forexample, the sympathetic nerves to the kidney traverse the sympatheticchain along the spine and synapse in the celiac ganglia, then proceedingto innervate the kidney with the post-ganglionic fibers. Within therenal nerves, which travel along the renal hila, are the post-ganglionicsympathetic nerves and the afferent nerves from the kidney. The afferentnerves deliver information from the kidneys back to the sympatheticnervous system and their ablation is at least partially responsible forthe improvement seen in blood pressure after renal nerve ablation. Ithas also been suggested and partially proven experimentally that thebaroreceptor response at the level of the carotid sinus is mediated bythe renal artery afferent nerves such that loss of the renal arteryafferent nerve response blunts the response of the carotid baroreceptorsto changes in arterial blood pressure

It has been established in animal models that the heart failurecondition results in abnormally high sympathetic activation of thekidneys. An increase in renal sympathetic nerve activity leads toincreased removal of water and sodium from the body, as well asincreased renin secretion which stimulates aldosterone secretion fromthe adrenal gland. Increased renin secretion can lead tovasoconstriction of blood vessels supplying the kidneys, which leads toa decrease in renal blood flow. Reduction in sympathetic renal nerveactivity, e.g., via de-innervation, may reverse these processes.

Recent clinical work has shown that de-innervation of the renalsympathetic chain nerves can lead to long term reduction of the need forblood pressure medications and improvement in blood pressure (O'BrienLancet 2009 373; 9681 incorporated by reference). The device used inthis trial utilized highly localized radiofrequency (RF) ablation toablate the renal artery adventitia with the presumption that the nervessurrounding the renal artery are being treated as well. The procedure isperformed in essentially a blind fashion in that the exact location ofthe sympathetic nerves is not known prior to, during, or after theprocedure. In addition, the wall of the renal artery is invariablydamaged by the RF probe and patients whose vessels have a great deal ofatherosclerosis cannot be treated safely. In addition, depending on thedistance of the nerves from the vessel wall, the energy may notconsistently lead to ablation or interruption. Finally, the use ofinternal catheters may not allow for treatment inside the kidney orinside the aorta if more selective or less selective blockade of therenal sympathetic nerves is desired.

Ultrasound is a cyclically generated sound pressure wave with afrequency greater than the upper limit of human hearing . . . 20kilohertz (kHz). In medicine, ultrasound is widely utilized because ofits ability to penetrate tissues. Reflection of the sound waves revealsa signature of the underlying tissues and as such, ultrasound can beused extensively for diagnostics and potentially therapeutics as well inthe medical field. As a therapy, ultrasound has the ability to bothpenetrate tissues and can be focused to create ablation zones. Becauseof its simultaneous ability to image, ultrasound can be utilized forprecise targeting of lesions inside the body.

Ultrasound can be utilized for its forward propagating waves andresulting reflected waves or where energy deposition in the tissue andeither heating or slight disruption of the tissues is desired. Forexample, rather than relying on reflections for imaging, lower frequencyultrasonic beams (e.g. <1 MHz) can be focused at a depth within tissue,creating a heating zone or a defined region of cavitation in whichmicro-bubbles are created, cell membranes are opened to admit bioactivemolecules, or damage is otherwise created in the tissue. These featuresof ultrasound generally utilize frequencies in the 0.25 Megahertz (MHz)to 10 MHz range. Focusing is or may be required so that the surface ofthe tissue is not excessively injured or heated by single beams.

SONAR is an acronym for sound navigation and ranging and is a method ofacoustic localization. Sound waves are transmitted through a medium andthe time for the sound to reflect back to the transmitter is indicativeof the position of the object of interest. Doppler signals are generatedby a moving object. The change in the forward and reflected wave resultsin a velocity for the object.

Cross-sectional imaging is utilized to visualize the internal anatomy ofpatients via radiation (CT) or magnetic fields (MRI). Ultrasound canalso be utilized to obtain cross-sections of specific regions but onlyat high frequencies; therefore, ultrasound is typically limited toimaging superficial body regions. CT and MRI are often more amenable tocross sectional imaging because the radiations penetrate well intotissues. In addition, the scale of the body regions is maintained suchthat the anatomy within the coordinate references remains intactrelative to one another; that is, distances between structures can bemeasured. With ultrasound, scaling can be more difficult because ofunequal penetration as the waves propagate deeper through the tissue. CTscans and MRIs and even ultrasound devices can be utilized to createthree dimensional representations and reconstructed cross-sectionalimages of patients; anatomy can be placed in a coordinate referenceframe using a three dimensional representation. Once in the referenceframe, energy devices (transducers) can be placed in positions andenergy emitting devices directed such that specific regions of the bodyare targeted. Once knowledge of the transducer position is knownrelative to the position of the target in the patient body, energy canbe delivered to the target.

In one embodiment, ultrasound is focused on the region of the renalarteries from outside the patient; the ultrasound is delivered frommultiple angles to the target allowing the current invention to overcomemany of the deficiencies in previous methods and devices put forward toablate renal sympathetic nerves which surround the renal arteries.

Specifically, one embodiment of this invention allows for precisevisualization of the ablation zone so that the operator can be confidentthat the correct region is ablated and that the incorrect region is notablated. Because some embodiments do not require a puncture in the skin,they are considerably less invasive, which is more palatable and saferfrom the patient standpoint. Moreover, unusual anatomies andatherosclerotic vessels can be treated using external energytriangulated on the renal arteries to affect the sympathetic andafferent nerves to and from the kidney respectively.

With reference to FIG. 1 a, the human renal anatomy includes the kidneys100 which are supplied with oxygenated blood by the renal arteries 200and are connected to the heart via the abdominal aorta 300. Deoxygenatedblood flows from the kidneys to the heart via the renal veins (notshown) and thence the inferior vena cava (not shown). The renal anatomyincludes the cortex, the medulla, and the hilum. Blood is delivered tothe cortex where it filters through the glomeruli and is then deliveredto the medulla where it is further filtered through a series ofreabsorption and filtration steps in the loops of henle and individualnephrons. The hila are the regions where the major vessels and nervestravel to and from the kidneys.

Energy transducers 500 (FIG. 1 a) deliver energy transcutaneously to theregion of the sympathetic ganglia 520 or the post-ganglionic renalnerves 150 or the nerves leading to the adrenal gland 400. The energy isgenerated from outside the patient, from multiple directions, andthrough the skin to the region of the renal nerves which surround therenal artery 640. The energy can be focused or non-focused but in onepreferred embodiment, the energy is focused with high intensity focusedultrasound (HIFU). Focusing occurs by delivering energy from at leasttwo different angles through the skin to meet at a focal point where thehighest energy intensity occurs. At this spot, a therapy is deliveredand the therapy can be sub-threshold nerve interruption, ablation(complete interruption) of the nerves, or targeted drug delivery. Toablate the nerves, temperatures greater than 40 degrees should begenerated for a time period greater than several minutes. If thetemperature is increased beyond 50-60 degrees, the time required forheating is decreased considerably. In some embodiments, an imagingmodality is included as well in the system.

The delivered energy can be ionizing or non-ionizing energy. Forms ofnon-ionizing energy can include electromagnetic energy, radiofrequencyenergy, and light based energy. Forms of ionizing energy include x-ray,proton beam, gamma rays, electron beams, and alpha rays. In someembodiments, the energy modalities are combined. For example, heatablation of the nerves is performed and then ionizing radiation isdelivered to the region to prevent re-growth of the nerves.

Alternatively, ionizing radiation is applied first as an ablationmodality and then heat applied afterward in the case of re-growth of thetissue as re-radiation may not be possible. Ionizing radiation mayprevent or inhibit the re-growth of the nervous tissue around the vesselif there is indeed re-growth of the nervous tissue.

In some embodiments, external neuromodulation is performed in which lowenergy ultrasound is applied to the nerve region to modulate the nerves.For example, it has been shown in the past that low intensity (e.g.non-thermal) ultrasound can affect nerves at powers which range from30-500 mW/Cm² whereas HIFU (thermal modulation), by definition generatesheat at a focus, requires power levels exceeding 1000 W/Cm². The actualpower flux to the region to be ablated is dependent on the environmentincluding surrounding blood flow and other structures. With lowintensity ultrasound, the energy does not have to be so strictly focusedto the target because it's a non-ablative energy; that is, the vibrationor mechanical pressure may be the effector energy and the target mayhave a different threshold for effect depending on the tissue. However,even low energy ultrasound may require focusing if excessive heat to theskin is a worry or if there are other susceptible structures in the pathand only a pinpoint region of therapy is desired.

In FIG. 1 a, and in one embodiment, a renal artery 640 is detected withthe assistance of imaging techniques 600 such as Doppler ultrasound,MRI, or a CT scan. With an image of the region to be treated,measurements in multiple directions on a series of slices can beperformed so as to create a three-dimensional representation of the areaof interest. By detecting the position of the renal arteries from morethan one angle via Doppler triangulation (for example) or anothertriangulation technique, a three dimensional positional map can becreated and the renal artery can be mapped into a coordinate referenceframe. In this respect, given that the renal nerves surround the renalblood vessels in the hilum, locating the direction and lengths of theblood vessels in three dimensional coordinate reference is thepredominant component of the procedure to target the sympathetic nerves.Within the three dimensional reference frame, a pattern of energy can beapplied to the vicinity of the renal artery from a device well outsidethe vicinity (and outside of the patient altogether) based on knowledgeof the coordinate reference frame.

For example, once the renal artery is placed in the coordinate referenceframe with the origin of the energy delivery device, an algorithm isutilized to localize the delivery of focused ultrasound to heat or applymechanical energy to the adventitia and surrounding regions of theartery which contain sympathetic nerves to the kidney and afferentnerves from the kidney, thereby decreasing the sympathetic stimulus tothe kidney and its afferent signaling back to the autonomic nervoussystem; affecting these targets will modulate the propensity towardhypertension which would otherwise occur. The ultrasonic energy deliverycan be modeled mathematically by predicting the wave dissipation usingthe distances and measurements taken with the imaging modalities of thetissues and path lengths.

Imaging 600 of the sympathetic nerves or the sympathetic region (thetarget) is also utilized so as to assess the direction and orientationof the transducers relative to the target 620. Continuous feedback ofthe position of the transducers 500 relative to the target 150 isprovided by the imaging system in which the coordinate space of theimaging system. The imaging may be a cross-sectional imaging technologysuch as CT or MRI or it may be an ultrasound imaging technology whichyields faster real time imaging. In some embodiments, the imaging may bea combination of technologies such as the fusion of MRI/CT andultrasound.

In the example of fusion, cross-sectional imaging (e.g. MRI/CT) isutilized to place the body of the patient in a three dimensionalcoordinate frame and then ultrasound is linked to the three dimensionalreference frame and utilized to track the patient's body in real timeunder the ultrasound linked to the cross-sectional imaging. The lack ofresolution provided by the ultrasound is made up for by thecross-sectional imaging since only a few consistent anatomic landmarksare required for an ultrasound image to be linked to the MRI image. Asthe body moves under the ultrasound, the progressively new ultrasoundimages are linked to the MRI images and therefore MRI “movement” can beseen at a frequency not otherwise available to an MRI series.

In one embodiment, ultrasound is the energy used to inhibit nerveconduction in the sympathetic nerves. In one embodiment, focusedultrasound (HIFU) is the energy used to inhibit sympathetic stimulationof the kidney by delivering waves from a position external to the bodyof a patient and focusing the waves on the sympathetic nerves on theinside of the patient and which surround the renal artery of thepatient. As is depicted in FIG. 3, transducers 900 can emit ultrasoundenergy to the region of the renal sympathetic nerves at the renalpedicle. As shown in FIG. 1 c, an image of the renal artery 620 using anultrasound, MRI, or CT scan can be utilized to determine the position ofthe kidney 610 and the renal artery 620. Doppler ultrasound can be usedto determine the location and direction of a Doppler signal from anartery and therefore enable the arteries and hence the sympatheticnerves around the artery to be much more visible so as to process theimages and then utilize focused external energy to pinpoint the locationand therapy of the sympathetic nerves. FIG. 1 a also depicts thedelivery of focused energy to the sympathetic nerve trunks which runalong the vertebral column; the renal artery efferent nerves travel inthese trunks. In another embodiment, ablation of the dorsal roots at thelevel of the ganglia or dorsal root nerves at T9-T11 (through which theafferent renal nerves travel) would produce the same or similar effectto ablation at the level of the renal arteries.

FIG. 1 b illustrates the application of ionizing energy to the region ofthe sympathetic nerves on the renal arteries 620 or renal veins. Ingeneral, energy levels of greater than 20 Gy (Grey) are required forlinear accelerators or low energy x-ray machines to ablate nervoustissue using ionizing energy; however, lower energy are required tostun, inhibit nervous tissue, or prevent regrowth of nervous tissue; insome embodiment, energy levels as low as 2-5 Gy or 5-10 Gy or 10 10-15Gy are delivered in a single or fractionated doses.

Combinations of ionizing energy and other forms of energy can beutilized in this embodiment as well so as to prevent re-growth of thenervous tissue.

FIG. 2 illustrates the renal anatomy and surrounding anatomy withgreater detail in that organs such as the stomach are shown in itsanatomic position overlying the abdominal aorta and renal arteries. Inthis embodiment, energy is delivered through the stomach to reach anarea behind the stomach. In this embodiment, the stomach is utilized asa conduit to access the celiac ganglion, a region which would otherwisebe difficult to reach. The aorta 705 is shown underneath the stomach andthe celiac ganglion 710 is depicted surrounding the superior mesentericartery and aorta. A transorally placed tube 720 is placed through theesophagus and into the stomach. The tube overlies the celiac ganglionwhen placed in the stomach and can therefore be used to deliversympatholytic devices or pharmaceuticals which inhibit or stimulate theautonomic celiac ganglia behind the stomach; these therapies would bedelivered via transabdominal ultrasound or fluoroscopic guidance (forimaging) through the stomach. Similar therapies can be delivered to theinferior mesenteric ganglion, renal nerves, or sympathetic nervestraveling along the aorta through the stomach or other portion of thegastrointestinal tract. The Energy delivery transducers 730,731 aredepicted external to the patient and can be utilized to augment thetherapy being delivered through the stomach to the celiac ganglion.

Temporary neurostimulators can also be placed through the tube, such as,for example, in an ICU setting where temporary blockage of the autonomicganglia may be required. Temporary neurostimulators can be used to overpace the celiac ganglion nerve fibers and inhibit their function as anerve synapse. Inhibition of the celiac ganglion may achieve a similarfunction as ablation or modulation of the sympathetic nerves around therenal arteries. That is, the decrease in the sympathetic activity to thekidneys (now obtained with a more proximal inhibition) leads to thelowering of blood pressure in the patient by decreasing the degree ofsympathetic outflow from the sympathetic nerve terminals. In the celiacganglia, the blood pressure lowering effect is more profound given thatthe celiac ganglia are pre-ganglionic and have more nerve fibers to agreater number of regions than each renal nerve.

FIG. 3 illustrates the renal anatomy more specifically in that the renalnerves 910 extending longitudinally along the renal artery, are locatedgenerally within, or just outside the adventitia, of the outer portionof the artery. Arteries are typically composed of three layers: thefirst is the intimal, the second is the media, and the third is theadventitia. The outer layer, the adventitia, is a fibrous tissue whichcontains blood vessels and nerves. The renal nerves are generallypostganglionic sympathetic nerves although there are some ganglia whichexist distal to the takeoff from the aorta such that some of the nervefibers along the renal artery are in fact pre-ganglionic. By the timethe fibers reach the kidney, the majority of the fibers arepost-ganglionic.

As shown in FIG. 3 a, energy generators 900 deliver energy to the renalnerves accompanying the renal artery, depositing energy from multipledirections to target inhibition of the renal nerve complex. The energygenerators can deliver ultrasound energy, ionizing radiation, light(photon) therapy, or microwave energy to the region. The energy can benon-focused in the case where a pharmaceutical agent is targeted to theregion to be ablated or modulated. Preferably, however, the energy isfocused, being applied from multiple angles from outside the body of thepatient to reach the region of interest (e.g. sympathetic nervessurrounding blood vessels). The energy transducers 900 are placed in anX-Y-Z coordinate reference frame 950 (FIG. 3 b), as are the organs suchas the kidneys. Once in the coordinate reference frame, cross-sectionalimaging using MRI, CT scan, and/or ultrasound is utilized to couple theinternal anatomy to the energy transducers. The transducers 900 in thisembodiment are focused on the region of the renal nerves at the level ofthe renal blood vessels, the arteries and veins.

When applying ultrasonic energy across the skin to the renal arteryregion, energy densities of potentially over 1 MW/cm² might be requiredso as to reach the region of interest. The energy may be pulsed acrossthe skin but for application of heat, the transducers must be focused;otherwise the skin and underlying tissues will receive too much heat.Under imaging with MRI, temperature can be measured with the MRI image.When low energy ultrasound is applied to the region, energy densities inthe range of 50 mW/cm² to 500 mW/cm² may be applied. Low energyultrasound may be enough to stun or partially inhibit the renal nerves.High intensity ultrasound applied to the region with only a few degreesof temperature rise may have the same effect. In some of theembodiments, cooling may be applied to the skin if the temperature riseis deemed too large to be acceptable. Alternatively, the ultrasoundtransducers can be pulsed or can be alternated with another set oftransducers to effectively spread the heat across the surface of theskin.

In one method of altering the physiologic process of renal sympatheticexcitation, the region around the renal arteries is imaged using CTscan, MRI, thermography, infrared imaging, pet imaging, SPECT imaging,or ultrasound, and the images are placed into a three dimensionalcoordinate reference frame. Energy transducers which can deliverultrasound, light, radiation, ionizing radiation, or microwave energyare placed in the same three-dimensional reference frame as the renalarteries at which time an algorithm can determine how to direct thetransducers to deliver energy to the region of the nerves. The algorithmconsists of a targeting feature (planning feature) which allows forprediction of the position and energy deposition of the energy leavingthe transducer. Once the three dimensional coordinate reference framesare linked or coupled, the planning and prediction algorithm can be usedto precisely position the energy beams at a target in the body.

The original imaging utilized to locate the renal sympathetic region canbe used to track the motion of the region during treatment. For example,the imaging technology used at time zero is taken as the baseline scanand subsequent scans at time t1 are compared to the baseline scan. Thefrequency of updates can range from a single scan every few seconds tomany scans per second. With ultrasound as the imaging technology, thelocation might be updated at a rate greater than 50 Hz and up to severalhundred Hz. With MRI as the imaging modality, the imaging refresh ratemight be closer to 30 Hz. In other embodiments, internally placedfiducials transmit positional information at a high frequency and thisinformation is utilized to fuse the target with an initial externalimaging apparatus.

A test dose of energy can be applied to the renal sympathetic region andthen a test performed to determine if there was an effect. For example,a small amount of heat can be delivered to the region of the sympatheticnerves and then a test of sympathetic activity such as microneurometry(detection of sympathetic nerve activity around muscles which correlateswith heartbeats) can be performed. Past research has shown that thesympathetic nerves to the peripheral muscles are affected byinterruption of the renal afferent nerves. The temperature rise with thesmall degree of heat can be determined through the use of MRIthermometry and the temperature rise can be determined or limited to anamount which is reversible.

Alternatively, ultrasonic imaging can be utilized to determine theapproximate temperature rise of the tissue region. The speed ofultrasonic waves is dependent on temperature and therefore the relativespeed of the ultrasound transmission from a region being heated willdepend on the temperature, therefore providing measurable variables tomonitor. In some embodiments, microbubbles are utilized to determine therise in temperature. Microbubbles expand and then degrade when exposedto increasing temperature so that they can then predict the temperatureof the region being heated. A technique called ultrasound elastographyan also be utilized. In this embodiment, tissue elastography isdependent on temperature so the elastography may be utilized to trackcreatures.

In another embodiment, a test may be performed on the baroreceptorcomplex at the region of the carotid artery bifurcation. After the testdose of energy is applied to the renal artery complex, pressure can beapplied to the carotid artery complex; typically, with an intactbaroreceptor complex, the systemic blood pressure would decrease afterapplication of pressure to the carotid artery.

Other regions of the autonomic nervous system can also be affecteddirectly by the technology in this invention by applying energy from oneregion to another. For example, FIG. 4 illustrates a system in whichexternal energy 1020 is applied to a portion of the autonomic nervoussystem, the carotid body complex 1000, through the internal jugular vein1005, and to the carotid body 1000 and/or vagus nerve 1021 region.Ablative energy or electrical stimulation energy can be utilized toaffect the transmission of signals to and from these nerves. Thetransmission in this complex can be augmented, interrupted, inhibitedwith over-stimulation, or a combination of these effects via energy(e.g. ultrasound, electrical stimulation, etc.)

A catheter 1010 is advanced into the internal jugular vein 1005 and whenin position, stimulation or ablative energy is directed toward theautonomic nerves, the vagus nerve, and the carotid sinus from thecatheter position in the venous system.

This therapy can be delivered on an acute basis such as for example inan ICU or critical care setting. In such a case, the therapy would beacute and intermittent, with the source outside the patient and thecatheter within the patient as shown in FIG. 4. The therapy can beutilized during times of stress for the patient such that thesympathetic system is slowed down. After the intensive care admission isnearing a close, the catheter and unit can be removed from the patient.

FIGS. 5 a-b illustrates the eye in close up detail with sympatheticnerves surrounding the posterior of the eye. In the eye, glaucoma is aproblem of world-wide import. The most commonly prescribed medication totreat glaucoma is timoptic, which is a non-selective β1 and β2(adrenergic) antagonist. Compliance with this pharmaceutical is a majorproblem and limits its effectiveness in preventing the complications ofglaucoma, the major complication being progression of visualdysfunction.

Ultrasound, or other energy transducers 7000, can be applied to focusenergy from an external region (e.g. a distance from the eye in anexternal location) anterior to the eye or to a region posteriorly behindthe eye 2500 on the sympathetic 2010 or parasympathetic ganglia, all ofwhich will affect lowering of intra-ocular pressure. The energytransducers 7000 apply ablative or near ablative energy to theadventitia of the blood vessel.

FIG. 5 b depicts the anatomy behind the eye. In this illustration, acatheter 2000 is tunneled through the vasculature to the region of thesympathetic nerves surrounding the arteries of the eye 2010 and utilizedto ablate, stun, or otherwise modulate the efferent and/or afferentnerves through the wall of the vasculature.

FIG. 6 illustrates an overall schematic of the renal artery collectingsystem. The individual nerves of the autonomic nervous system typicallyfollow the body vasculature and they are shown in close proximity to therenal artery as the artery enters the kidney 3100 proper.

In one embodiment, selective lesions, constrictions or implants 3200 areplaced in the calyces of the kidney to control or impede blood flow tospecific regions of the kidney. Such lesions or implants can be placedon the arterial 3010 or venous sides 3220 of the kidney. In someembodiments, the lesions/implants are created so as to selectively blockcertain portions of the sympathetic nerves within the kidney. Thelesions also may be positioned so as to ablate regions of the kidneywhich produce hormones, such as renin, which can be detrimental to apatient in excess. The implants or constrictions can be placed in theaorta 3210 or the renal vein 3220. In the renal vein, the implants canresult in an increased pressure within the kidney to prevent thedownward spiral of systolic heart failure described above. That is, oncethe pressure in the kidney is restored by increased venous pressure, therelative renal hypotension signaling to retain electrolytes and waterwill not be present any longer. In one embodiment, a stent which createsa stenosis is implanted using a catheter delivery system 3000. Inanother embodiment, a stricture is created using heat delivered eitherexternally or internally.

FIG. 7 b depicts at least partial ablation of the renal sympatheticnerves 4400 to the kidney using an imaging system such as an MRI machineor CT scanner 4000. The MRI/CT scan can be linked to a focusedultrasound (HIFU) machine to perform the ablations of the sympatheticnerves 4400 around the region of the renal artery 4500. The MRI/CT scanperforms the imaging 4010 and transmits data (e.g. three dimensionalrepresentations of the regions of interest) to the ultrasound controllerwhich then direct the ultrasound to target the region of interest withlow intensity ultrasound (50-1000 mW/cm2) heat (>1000 mW/cm2),cavitation, or a combination of these modalities and/or includingintroduction of enhancing agents locally or systemically (sonodynamictherapy). Optionally, a doppler ultrasound or other 3D/4D ultrasound isperformed and the data pushed to the MRI system to assist withlocalization of the pathology; alternatively, the ultrasound data areutilized to directly control the direction of the energy being used totarget the physiologic processes and CT/MRI is not obtained. Using thisimaging and ablation system from a position external to a patient, manyregions of the kidney can be treated such as the internal calyces, thecortex, the medulla, the hilum and the region near to the aorta.

Further parameters which can be measured include temperature via thermalspectroscopy using MRI or ultrasound thermometry; thermal imaging is awell-known feature of MRI scanners; the data for thermal spectroscopyexists within the MRI scan and can be extrapolated from the recordeddata in real time by comparing regions of interest before and after orduring treatment. Temperature data overlaid on the MRI scan enables theoperator of the machine to visualize the increase in temperature andtherefore the location of the heating to insure that the correct regionhas indeed been ablated and that excessive energy is not applied to theregion. Having temperature data also enables control of the ablationfield as far as applying the correct temperature for ablation to thenerves. Furthermore, other spectroscopic parameters can be determinedusing the MRI scan such as oxygenation, blood flow, or other physiologicand functional parameters.

MRI scanners 4000 generally consist of a magnet and an RF coil. Themagnet might be an electromagnet or a permanent magnet. The coil istypically a copper coil which generates a radiofrequency field.Recently, permanent magnets have been utilized to create scanners whichare able to be used in almost any setting, for example a private officesetting. Office based MRI scanners enable imaging to be performedquickly in the convenience of a physicians offices as well as requiringless magnetic force (less than 0.5 Tesla) and as a consequence, lessshielding. The lower tesla magnets also provides for special advantagesas far as diversity of imaging and resolution of certain features.Importantly, the permanent magnet MRI scanners are open scanners and donot encapsulate the patient during the scan.

In one embodiment, a permanent magnet MRI is utilized to obtain an MRIimage of the region of interest 4010 (FIG. 7 b). High intensity focused4100 ultrasound is used to target the region of interest 4600 identifiedusing the MRI (FIGS. 7 a and 7 c).

Image 4010 is monitored by a health care professional to ensure that theregion of interest is being treated and can stop the therapy if theregion is not being treated. Alternatively, an imaging algorithm can beinitiated in which the region of interest is identified and thensubsequent images are compared to the initial demarcated region ofinterest.

Perhaps, most importantly, with MRI, the region around the renalarteries can be easily imaged as can any other region such as the eye,brain, prostate, breast, liver, colon, spleen, aorta, hip, knee, spine,venous tree, and pancreas. The imaging from the MRI can be utilized toprecisely focus the ultrasound beam to the region of interest around therenal arteries or elsewhere in the body. With MRI, the actual nerves tobe modified or modulated can be directly visualized and targeted withthe energy delivered through the body from the ultrasound transducers.

FIG. 7 d depicts a method of treating a region with high intensityfocused ultrasound (HIFU). Imaging with an MRI 4520 or Dopplerultrasound 4510 (or preferably both) is performed. MRI can be used todirectly or indirectly (e.g. using functional MRI or spectroscopy) tovisualize the sympathetic nerves. T1 weighted or T2 weighted images canbe obtained using the MRI scanner. In addition to anatomic imaging, theMRI scanner can also obtain temperature data regarding the effectivenessof the ablation zone as well as the degree to which the zone is beingheated and which parts of the zones are being heated. Otherspectroscopic parameters can be added as well such as blood flow andeven nerve activity. Ultrasound can be used to add blood flow to theimages using Doppler imaging. The spectroscopic data can be augmented byimaging moieties such as particles, imaging agents, or particles coupledto imaging agents which are injected into the patient intravenously, orlocally, and proximal to the region of the renal arteries; these imagingmoieties may be visualized on MRI, ultrasound, or CT scan. Ultrasoundcan also be utilized to determine information regarding heating. Thereflectance of the ultrasonic waves changes as the temperature of thetissue changes. By comparing the initial images with the subsequentimages after heating, the temperature changes can be determined.

In one embodiment, the kidneys are detected by the cross-sectionalimaging modality such as MRI, ultrasound, or CT scan. Next, the imagingdata is placed into a three dimensional coordinate system which islinked to one or more ultrasound (e.g. HIFU) transducers which focusultrasound onto the region of the renal arteries in the coordinateframe. The linking, or coupling, of the imaging to the therapeutictransducers is accomplished by determining the 3 dimensional position ofthe target by creating an anatomic model. The transducers are placed ina relative three dimensional coordinate frame as well. For example, thetransducers can be placed in the imaging field during the MRI or CT scansuch that the cross-sectional pictures include the transducers.Alternatively, ultrasound is utilized and the ultrasound image can bedirectly correlated to the origin of the imaging transducer. Thetherapeutic transducer in some embodiments is the same as the imagingtransducer and therefore the therapeutic transducer is by definitioncoupled in a coordinate reference once the imaging transducercoordinates are known. If the therapeutic transducer and the imagingtransducer are different devices, then they can be coupled by knowledgeof the relative position of the two devices. The region of interest(ROI) is highlighted in a software algorithm . . . for example, therenal arteries, the calyces, the medullary region, the cortex, the renalhila, the celiac ganglia, the aorta, or any of the veins of the venoussystem as well. In another embodiment, the adrenal gland, the vesselstraveling to the adrenal gland, or the autonomic nerves traveling to theadrenal gland are targeted with focused ultrasound and then either themedulla or the cortex of the adrenal gland or the nerves and arteriesleading to the gland are partially or fully ablated with ultrasonicenergy.

Once the transducers are energized after the region is targeted, thetissue is heated 4560 and a technique such as MRI thermography 4570 orultrasound thermography is utilized to determine the tissue temperature.During the assessment of temperature, the anatomic data from the MRIscan or the Doppler is then referenced to ensure proper positioning andthe degree of energy transduction is again further assessed by themodeling algorithm 4545 to set the parameters for the energy transducers4550.

Ablation can also be augmented using agents such as magneticnanoparticles or liposomal nanoparticles which are responsive to aradiofrequency field generated by a magnet. These particles can beselectively heated by the magnetic field. The particles can also beenhanced such that they will target specific organs and tissues usingtargeting moieties such as antibodies, peptides, etc. In addition to thedelivery of heat, the particles can be activated to deliver drug orbioactive, or imaging agent at the region at which action is desired.

The addition of Doppler ultrasound 4510 may be provided as well. Therenal arteries are (if renal arteries are the target) placed in a 3Dcoordinate reference frame 4530 using a software algorithm with orwithout the help of fiducial markers. Data is supplied to ultrasoundtransducers 4540 from a heat modeling algorithm 4545 and the transducersare energized with the appropriate phase and power to heat the region ofthe renal artery to between 40 degrees C. and 90 degrees C. within atime span of several minutes. The ultrasound transducers may havefrequencies below 1 megahertz (MHz), from 1-20 MHz, or above 30 Mhz. Thetransducers may be in the form of a phased array, either linear orcurved, or the transducers may be mechanically moved so as to focusultrasound to the target of interest. In addition, MRI thermography 4570can be utilized so as to obtain the actual temperature of the tissuebeing heated. These data can be further fed back to the system to slowdown or speed up the process of ablation 4560 via the transducers 4550.

Aside from focused ultrasound, ultrasonic waves can be utilized directlyto either heat an area or to activate pharmaceuticals in the region ofinterest. There are several methodologies to enhance drug delivery usingfocused ultrasound. For example, particles can release pharmaceuticalwhen they are heated by the magnetic field. Liposomes can release apayload when they are activated with focused ultrasound. Ultrasoundwaves have a natural focusing ability if a transducer is placed in thevicinity of the target and the target contains an activatable moietysuch as a bioactive drug or material (e.g. a nanoparticle sensitive toacoustic waves). Examples of sonodynamically activated moieties includesome porphyrin derivatives.

So as to test the region of interest and the potential physiologiceffect of ablation in that region, the region can be partially heatedwith the focused ultrasound to stun or partially ablate the nerves.Next, a physiologic test such as the testing of blood pressure ormeasuring norepinephrine levels in the blood can be performed to ensurethat the correct region was indeed targeted for ablation.

In another embodiment, a fiducial is utilized to demarcate the region ofinterest. For example, the fiducial can be an implanted fiducial, afiducial or device placed in the blood vessels, or a device placedpercutaneously through a catheterization or other procedure. Thefiducial can also be a bone, such as a rib, or another internal organ,for example, the liver. In one embodiment, the fiducial is a beacon oror balloon or balloon with a beacon which is detectable via ultrasound.In one embodiment, the blood flow in the renal arteries, detected viaDoppler, is the fiducial and its relative direction is determined viaDoppler analysis. Next, the renal arteries, and specifically, the regionaround the renal arteries are placed into a three dimensional coordinateframe utilizing the internal fiducials. A variant of global positioningsystem technology can be utilized to track the fiducials within theartery or around the arteries. The three dimensional coordinate frame istransmitted to the therapeutic ultrasound transducers and then thetransducers and anatomy are coupled to the same coordinate frame.

In one embodiment, a virtual fiducial is created. For example, in thecase of a blood vessels such as the renal artery, an image of the bloodvessel using ultrasound can be obtained which correlates to the bloodvessel being viewed in direct cross section (1700; FIG. 17 e). When thevessel is viewed in this type of view, the center of the vessel can bealigned with the center of an ultrasound array (e.g. HIFU array 1600, asshown in FIG. 17 e) and the transducers can be focused and applied tothe vessel, applying heat to regions 1680 around the vessels 1700 (FIGS.17 e and 17 f). With different positions of the transducers 1610 along acircumference or hemisphere 1650, varying focal points can be created1620, 1630, 1640. The directionality of the transducers allows for alesion which runs lengthwise along the vessel 1700. Thus a longitudinallesion 1150 can be produced along the artery to insure maximalinhibition of nerve function (FIG. 17 b). FIG. 17 d illustrates atreatment method 1500 that involves (1) determining patient positionwith Doppler B scan such that a cross section of the artery may bedetermined relative to a focusing of the HIFU (item 1510), (2) obtainingcoordinate data from Doppler shift (item 1530), and (3) applyingspherically-focused ultrasound array lengthwise along the artery (item1520).

In this method of treatment, an artery such as a renal artery is viewedin cross-section or close to a cross-section under ultrasound guidance.In this position, the blood vessel is parallel to the axis of thespherical transducer to facilitate lesion production. The ultrasoundtransducers setup 1600 has previously been calibrated to create focallesions 1620, 1630, 1640 along the artery if the artery is incross-section 1680.

In one embodiment, the fiducial is an intravascular fiducial such as aballoon. The balloon is detectable via radiotransmitter within theballoon which is detectable by the external therapeutic transducers. Theballoon can have three transducers, each capable of relaying theirposition so that the balloon can be placed in a three dimensionalcoordinate reference. Once the balloon is placed into the samecoordinate frame as the external transducers using the transmittingbeacon, the energy transducing devices can deliver energy (e.g. focusedultrasound) to the blood vessel (e.g. the renal arteries) or the regionsurrounding the blood vessels (e.g. the renal nerves). The balloon andtransmitters also enable the ability to definitively track thevasculature in the case of movement (e.g. the renal arteries). Inanother embodiment, the balloon measures temperature or is a conduit forcoolant applied during the heating of the artery or nerves.

Delivery of therapeutic ultrasound energy is delivered to the tissueinside the body via ultrasound transducers directed to deliver energy tothe target in the coordinate frame.

Once the target is placed in the coordinate frame and the energydelivery is begun, it is important to maintain targeting of theposition, particularly when the target is a small region such as thesympathetic nerves. To this end, the position of the region of ablationis compared to its baseline position. The ongoing positional monitoringand information is fed into an algorithm which determines the newtargeting of the energy waves at the target. In one embodiment, if theposition is too far from the original position, then the energy deliveryis stopped and the patient repositioned. If the position is not too farfrom the original position, then the energy transducers can berepositioned either mechanically (e.g. through physical movement) orelectrically via phased array (e.g. by changing the relative phase ofthe waves emanating from the transducers). In another embodiment,multiple transducers are placed on the patient in different positionsand each is turned on or off to result in the necessary energy delivery.

In addition to heat delivery, ultrasound can be utilized to delivercavitating energy which may enable drug delivery at certain frequencies.Cavitating energy can also lead to ablation of tissue at the area of thefocus. A systemic dose of a drug can be delivered to the region ofinterest and the region targeted with the cavitating or other forms ofultrasonic energy. Other types of therapeutic delivery modalitiesinclude ultrasound sensitive bubbles or radiation sensitivenanoparticles, all of which enhance the effect of the energy at thetarget of interest.

Ultrasound may also be utilized to create tumor vaccines in vivo. Inthis embodiment, sub-ablative doses of energy is applied to a tumor toinduce a stress response or to heat shock response to increase theanti-tumor or immune response to the tumor.

FIG. 8 a depicts a percutaneous procedure 5000 and device 5010 in whichthe region around the renal artery 5030 is approached through the skinand from an external position. A combination of imaging and ablation maybe performed to ablate the region around the renal artery to treathypertension, end stage renal disease, and heart failure. Probe 5010 ispositioned through the skin and in proximity to the kidney 5030. Theprobe may include sensors which detect heat or temperature or may enableaugmentation of the therapeutic energy delivery. Ablative, ionizingenergy, heat, or light may be applied to the region to inhibit thesympathetic nerves around the renal artery using the probe 510.Ultrasound, radiofrequency, microwave, direct heating elements, andballoons with heat or energy sources may be applied to the region of thesympathetic nerves. In one embodiment, the percutaneous procedure isperformed under MRI, CT, or ultrasound guidance to obtain localizationor information about the degree of heat being applied. A particularlypreferred embodiment would be to perform the procedure under guidancefrom an MRI scanner because the region being heated can be determinedanatomically in real time as well via temperature maps. As describedabove the images after heating can be compared to those at baseline andthe signals are compared at the different temperatures.

In one embodiment, selective regions of the kidney are ablated throughthe percutaneous access route; for example, regions which secretehormones which are detrimental to a patient or to the kidneys or otherorgans. Using energy applied external to the patient through the skinand from different angles affords the ability to target any region in oron the kidney or along the renal nerves or at the region of the adrenalgland, aorta, or sympathetic chain. This greater breadth in the numberof regions to be targeted is enabled by the combination of externalimaging and external delivery of the energy from a multitude of anglesthrough the skin of the patient to the target.

In a further embodiment, probe 5010 can be utilized to detecttemperature or motion of the region while the ultrasound transducers areapplying the energy to the region. A motion sensor, position beacon, oraccelerometer can be used to provide feedback for the HIFU transducers.In addition, an optional temperature or imaging modality may be placedon the probe 5010. The probe 5010 can also be used to locate theposition within the laparoscopic field for the ablations to beperformed.

In FIG. 8 b an intravascular device 5050 is depicted which appliesenergy to the region around the renal arteries 5055, 5060. Theintravascular devices can be utilized to apply radiofrequency,ultrasound (either focused or unfocused) energy to the renal artery andsurrounding regions. MRI or ultrasound or direct thermometry can befurther utilized to detect the region where the heat is being appliedwhile the intravascular catheter is in place.

Alternatively, in another embodiment, the devices 5050, 5055 can beutilized to direct the ultrasound to the correct place around the arteryas the HIFU transducers deliver the energy to the region. For example,the intravascular probe 5050 can be utilized as a homing beacon for theimaging technology utilized for the externally delivered HIFU.

In another embodiment, the physiologic process of arterial expansion istargeted. In FIG. 9 a, an ultrasound transducer is 6005 is placed nearthe wall of an aneurysm 6030. Ultrasonic energy is applied to the wall6030 of the aneurysm to thicken the wall and prevent further expansionof the aneurysm. In some embodiments, clot within the aneurysm istargeted as well so that the clot is broken up or dissolved with theultrasonic energy. Once the wall of the aneurysm is heated withultrasonic energy to a temperature of between 40 and 70 degrees, thecollagen, elastin, and other extracellular matrix in the wall willharden as it cools, thereby preventing the wall from further expansion.In another embodiment, a material is placed in the aneurysm sac and thefocused or non-focused ultrasound utilized to harden or otherwise inducethe material in the sac to stick to the aorta or clot in the aneurysmand thus close the aneurysm permanently. In one embodiment therefore, anultrasound catheter is placed in an aorta at the region of an aneurismwall or close to a material in an aneurysmal wall. The material can be aman-made material placed there by an operator or it can be material suchas thrombus which is in the aneurysm naturally. Ultrasound is applied tothe wall, or the material, resulting in hardening of the wall or of thematerial, strengthening the aneurysm wall and preventing expansion.

FIG. 9 b depicts a clot prevention device 6012 within a blood vesselsuch as the aorta or vena cava 6000. The ultrasound catheter 6005 isapplied to the clot prevention device (filter) 6012 so as to remove theclot from the device or to free the device 6012 from the wall of theblood vessel in order to remove it from the blood vessel 6000.

FIG. 9 c depicts a device and method in which the celiac plexus 6020close to the aorta 6000 is ablated or partially heated using heat energyfrom an ultrasonic energy source 6005 which can apply focused orunfocused sound waves 6007 at frequencies ranging from 20 kilohertz to 5Mhz. Full, or partial ablation of the celiac plexus 6020 can result in adecrease in blood pressure via a similar mechanism as in FIG. 9; theablation catheter is a focused ultrasound catheter but can also be adirect ultrasound, a microwave element, or a resistive heating element.

FIG. 10 depicts a method 6100 to treat a patient with high intensityfocused ultrasound (HIFU) 6130. In a first step, a CT and/or MRI scanand/or thermography and/or 3D ultrasound is performed 6110. A fiducialor other marking on the patient 6120 is optionally used to mark andtrack the patient. The fiducial can be an implanted fiducial, atemporary fiducial, or a fiducial intrinsic to the patient (e.g. bone)which can be imaged using the CT/MRI/Ultrasound devices 6010. Thefiducial can further be a temporary fiducial such as a cathetertemporarily placed in an artery or vein of a patient or a percutaneouslyplaced catheter. A planning step 6130 for the HIFU treatment isperformed in which baseline readings such as position of the organ andtemperature are determined; a HIFU treatment is then planned using amodel (e.g. finite element model) to predict heat transfer, or pressureto heat transfer, from the ultrasound transducers 6130.

The planning step 6130 includes determination of the positioning of theultrasound transducers as far as position of the focus in the patient.X, Y, Z, and three angular coordinates are used to determine theposition of the ultrasonic focus in the patient based on the crosssectional imaging 6110. The HIFU transducers might have their ownposition sensors built in so that the position relative to the targetcan be assessed. Alternatively, the HIFU transducers can be rigidlyfixed to the table on which the patient rests so that the coordinatesrelative to the table and the patient are easily obtainable. The flow ofheat is also modeled in the planning step 6130 so that the temperatureat a specific position with the ultrasound can be planned and predicted.For example, the pressure wave from the transducer is modeled as itpenetrates through the tissue to the target. For the most part, thetissue can be treated as water with a minimal loss due to interfaces.The relative power and phase of the ultrasonic wave at the target can bedetermined by the positional coupling between the probe and target. Aconvective heat transfer term is added to model heat transfer due toblood flow, particularly in the region of an artery. A conductive heattransfer term is also modeled in the equation for heat flow andtemperature.

Another variable which is considered in the planning step is the size ofthe lesion and the error in its position. In the ablation of smallregions such as nerves surrounding blood vessels, the temperature of theregions may need to be increased to a temperature of 60-90 degreesCelsius to permanently ablate nerves in the region. Temperatures of40-60 degrees may temporarily inhibit or block the nerves in theseregions and these temperatures can be used to determine that a patientwill respond to a specific treatment without permanently ablating thenerve region.

An error analysis is also performed during the treatment. Each elementof temperature and position contains an error variable which propagatesthrough the equation of the treatment. The errors are modeled to obtaina virtual representation of the temperature mapped to position. This mapis correlated to the position of the ultrasound transducers in thetreatment of the region of interest.

During the delivery of the treatment 6200, the patient may move, inwhich case the fiducials 6120 track the movement and the position of thetreatment zone is re-analyzed 6150 and the treatment is restarted or thetransducers are moved either mechanically or electrically to a new focusposition.

In another embodiment, a cross-sectional technique of imaging is used incombination with a modality such as ultrasound to create a fusion typeof image. The cross-sectional imaging is utilized to create a threedimensional data set of the anatomy. The ultrasound, providing twodimensional images, is linked to the three dimensional imaging providedby the cross-sectional machine through fiducial matches between theultrasound and the MRI. As a body portion moves within the ultrasoundfield, the corresponding data is determined (coupled to) thecross-sectional (e.g. MRI image) and a viewing station can show themovement in the three dimensional dataset. The ultrasound provides realtime images and the coupling to the MRI or other cross-sectional imagedepicts the ultrasound determined position in the three dimensionalspace.

FIGS. 11 a-11 c depict the treatment of another disease in the body of apatient, this time in the head of a patient. Subdural and epiduralhematomas occur as a result of bleeding of blood vessels in the dural orepidural spaces of the brain, spinal column, and scalp. FIG. 11 adepicts a CT or MRI scanner 7300 and a patient 7400 therein. An image isobtained of the brain 7420 using a CT or MRI scan (FIG. 11 b). The imageis utilized to couple the treatment zone 7100 to the ultrasound arraysutilized to heat the region. In one embodiment 7010, a subduralhematoma, either acute or chronic, is treated (FIG. 11 b). In anotherembodiment 7200, an epidural hematoma is treated (FIG. 11 c). In bothembodiments, the region of leaking capillaries and blood vessels areheated to stop the bleeding, or in the case of a chronic subduralhematoma, the oozing of the inflammatory capillaries.

In an exemplary embodiment of modulating physiologic processes, apatient 7400 with a subdural or epidural hematoma is chosen fortreatment and a CT scan or MRI 7300 is obtained of the treatment region.Treatment planning ensues and the chronic region of the epidural 7200 orsub-dural 7010 hematoma is targeted for treatment with the focusedultrasound 7100 transducer technology. Next the target of interest isplaced in a coordinate reference frame as are the ultrasoundtransducers. Therapy 7100 ensues once the two are couple together. Thefocused ultrasound heats the region of the hematoma to dissolve the clotand/or stop the leakage from the capillaries which lead to theaccumulation of fluid around the brain 7420. The technology can be usedin place of or in addition to a burr hole, which is a hole placedthrough the scalp to evacuate the fluid.

FIG. 12 depicts a laparoscopic based approach 8000 to the renal arteryregion in which the sympathetic nerves 8210 can be ligated, interrupted,or otherwise modulated. In laparoscopy, the abdomen of a patient isinsufflated and laparoscopic instruments introduced into the insufflatedabdomen. The retroperitoneum is accessible through a flank approach orthrough a transabdominal approach. A laparoscopic instrument 8200 with adistal tip 8220 can apply heat or another form of energy or deliver adrug to the region of the sympathetic nerves 8210. The laparoscopicimplement can also be utilized to ablate or alter the region of theceliac plexus 8300 and surrounding ganglia. The laparoscope can have anultrasound transducer attached, a temperature probe attached, amicrowave transducer attached, or a radiofrequency transducer attached.The laparoscope can be utilized to directly ablate or stun the nervessurrounding vessels or can be used to ablate or stun nerve ganglia whichtravel with the blood vessels.

FIG. 13 depicts an algorithm for the treatment of a region of interest.MRI and/or CT with or without a imaging agent 8410 can be utilized todemarcate the region of interest (for example, the ablation zone) andthen ablation 8420 can be performed around the zone identified by theagent using any of the modalities above. This algorithm is applicable toany of the therapeutic modalities described above including externalHIFU, laparoscopic instruments, intravascular catheters, percutaneouscatheters, as well as any of the treatment regions including the renalnerves, the eye, the kidneys, the aorta, or any of the other nervessurrounding peripheral arteries or veins. Imaging 8430 with CT, MRI,ultrasound, or PET can be utilized in real time. At such time whendestruction of the lesion is complete 8440, imaging with an imaging (forexample, a molecular imaging agent or a contrast agent such asgadolinium) agent 8410 can be performed again. The extent of ablationcan also be monitored by monitoring the temperature or the appearance ofthe ablated zone under an imaging modality. Once lesion destruction iscomplete 8440, the procedure is finished.

FIG. 14 depicts ablation in which specific nerve fibers of a nerve aretargeted using different temperature gradients or temperatures 8500. Forexample, if temperature is determined by MRI thermometry or with anothertechnique such as ultrasound, then the temperature can be kept at atemperature in which only certain nerve fibers are targeted fordestruction or inhibition. Alternatively, part or all of the nerve canbe turned off temporarily to then test the downstream effect of thenerve being turned off. For example, the sympathetic nerves around therenal artery can be turned off with a small amount of heat or otherenergy and then the effect can be determined. For example,norepinephrine levels in the blood or the stimulation effect of thenerves can be tested after temporary cessation of activity.

FIG. 15 depicts treatment 8600 of a vertebral body or intervertebraldisk 8610 in which nerves within 8640 or around the vertebral column8630 are targeted with ultrasound 8625 waves. In one embodiment, nervesaround the facet joints are targeted. In another embodiment, nervesleading to the disks or vertebral endplates are targeted.

FIG. 16 depicts a set of lesion types, sizes, and anatomies 8710 a-hwhich lead to de-innervation of the different portions of thesympathetic nerve tree. For example, the lesions can be annular, cigarshaped, linear, doughnut and/or spherical; the lesions can be placedaround the renal arteries 8705, inside the kidney 8710, and/or aroundthe aorta 8700. For example, the renal arterial tree 8700 comprisesrenal arteries 8705 and kidneys 8715. Lesions 8710 a-h are differenttypes of lesions which are created around the aorta 8700 and vasculartree.

FIG. 17 a depicts a multi-transducer HIFU device 1100 which applies afinite lesion 1150 along an artery 1140 (e.g. a renal artery) leading toa kidney 1130. The lesion can be spherical in shape, cigar shaped 1050,annular shaped 1050, or point shaped; however, in a preferredembodiment, the lesion runs along the length of the artery and has acigar shaped. This lesion is generated by a spherical type of ultrasoundarray in a preferred embodiment. FIG. 17 e depicts the pathway of thespherical or cylindrical type of ultrasound array 1600. Ultrasoundtransducers 1610 are aligned along the edge of a cylinder aimed so thatthey intersect at one or more focal spots 1620, 1630, 1640. Thetransducers 1610 are positioned along the cylinder 1650 such that someare closer to one focus or the other so that a range of distances to theartery is created. The patient and artery are positioned such that theartery centers 1700 co-localize with the center of the ultrasound array1600. Once the centers are co-localized, the HIFU energy can beactivated to create lesions along the length of the artery wall 1640,1620, 1630 at different depths and positions around the artery. Thenatural focusing of the transducers positioned along a cylinder as inFIG. 17 b is a lengthwise lesion 1150, longer than in thickness orheight, which will run along the length of an artery when the artery isplaced along the center axis of the cylinder. When viewed along a crosssection the nerve ablations (e.g., the ablation 1350 shown in the screen1300) are positioned along a clock face 1680 around the vessel 1340(FIGS. 17 c and 17 f).

Importantly, during treatment, a treatment workstation 1300 givesmultiple views of the treatment zone with both physical appearance andanatomy 1050. Physical modeling is performed in order to predict lesiondepth and the time to produce the lesion; this information is fed backto the ultrasound transducers 1100. The position of the lesion is alsoconstantly monitored in a three dimensional coordinate frame and thetransducer focus at lesions center 1150 continually updated.

In some embodiments, motion tracking prevents the lesion or patient frommoving too far out of the treatment zone during the ablation. If thepatient does move outside the treatment zone during the therapy, thenthe therapy can be stopped.

FIG. 18 depicts a micro-catheter 8810 which can be placed up into renalcalyces 8820; this catheter allows the operator to specifically ablateor stimulate 8830 regions of the kidney 8800. The catheter can be usedto further allow for targeting of the region around the renal arteriesand kidneys by providing additional imaging capability or by assistingin movement tracking or reflection of the ultrasound waves to create orposition the lesion. The catheter or device at or near the end of thecatheter may transmit signals outside the patient to direct an energydelivery device which delivers energy through the skin.

In one method, a micro catheter is delivered to the renal arteries andinto the branches of the renal arteries in the kidney. A signal isgenerated from the catheter into the kidney and out of the patient to anenergy delivery system. Based on the generated signal, the position ofthe catheter in a three dimensional coordinate reference is determinedand the energy source is activated to deliver energy to the regionindicated by the microcatheter.

Alternatively, specific regions of the kidney might be responsible forhormone excretion or other factors which lead to hypertension or otherdetrimental effects to the cardiovascular system.

FIG. 19 depicts the application of acoustic waves to the region of therenal artery 8910 and kidney 8920 using physically separated transducers8930, 8931. In contrast to the delivery method of FIG. 17, FIG. 19depicts delivery of ultrasound transverse to the renal arteries and notlongitudinal to the artery. In some embodiments, such delivery might beadvantageous if for example, a longitudinal view of the artery isunobtainable or a faster treatment paradigm is desirable. Thetransducers 8930, 8931 communicate with one another and are connected toa computer model of the region of interest being imaged (ROI), the ROIbased on an MRI scan performed just prior to the start of the procedureand throughout the procedure.

FIG. 20 depicts an alternative method 9000 and device to ablate therenal nerves 9015 or the nerves leading to the renal nerves at theaorta-renal artery osmium 9010. The intravascular device 9020 is placedinto the aorta 9050 and advanced to the region of the renal arteries9025. Energy is applied from the transducer 9020 and focused 9040 (inthe case of HIFU) to the region of the takeoff of the renal arteries9025 from the aorta 9050. This intravascular procedure can be guidedusing MRI and/or MRI thermometry or it can be guided using fluoroscopy,ultrasound, or MRI. Because the aorta is larger than the renal arteries,the HIFU catheter can be placed into the aorta directly. In addition,non-focused ultrasound can be applied to the region around the renalostium or higher in the aorta. Non-focused ultrasound in someembodiments may require cooling of the tissues surrounding the probeusing one or more coolants but in some embodiments, the blood of theaorta will take the place of the coolant; HIFU, or focused ultrasound,may not need the cooling because the waves are by definition focusedfrom different angles to the region around the aorta. The vena cava canalso be used as a conduit for the focused ultrasound transducer todeliver energy to the region.

FIG. 21 depicts an eyeball 9100. Also depicted are the zonules 9130 andultrasound transducer 9120. The transducer 9120 applies focusedultrasound energy to the region surrounding the zonules, or the zonulesthemselves, in order to tighten them such that a presbyopic patient canaccommodate. Similarly, heat to ciliary muscles, which then slows downthe outflow of aqueous humor at the region of interest so that thepressure within the eye cannot build up to a high level. The ultrasoundtransducer 9120 can also be utilized to deliver drug therapy to theregion of the lens, ciliary body, zonules, intravitreal cavity, anteriorcavity, posterior cavity, etc.

In some embodiments (FIG. 21 b), the ultrasonic transducers 9170 arefocused on the particular region of the eye so that tissues along thepath of the ultrasound are not damaged by the ultrasound and the focusregion and region of effect is the position where the waves meet in theeye. In one embodiment, the transducers are directed through the parsplana region of the eye to target the macula 9180 at the posterior pole9175 of the eye. This configuration might allow for heat, vibratorystimulation, drug delivery, gene delivery, augmentation of laser orionizing radiation therapy, etc.

FIG. 22 depicts a peripheral joint 9200 being treated. Ultrasoundtransducer 9210 emits waves toward the knee joint to block nerves 9260just underneath the bone periostium. Although a knee joint is depicted,it should be understood that many joints can be treated including smalljoints in the hand, intervertebral joints, the hip, the ankle, thewrist, and the shoulder.

FIG. 23 a-b depicts closure of a fallopian tube 9300 of a uterus 9320using externally applied ultrasound 9310 so as to prevent pregnancy. MRIor preferably ultrasound can be utilized for the imaging modality.Thermometry can be utilized as well so as to see the true ablation zonein real time. The fallopian tube 9300 can be visualized usingultrasound, MRI, CT scan or a laparoscope. Once the fallopian tube istargeted, external energy 9310, for example, ultrasound, can be utilizedto close the fallopian tube to prevent pregnancy.

In other embodiments, ultrasound is applied to the uterus or fallopiantubes to aid in pregnancy by improving the receptivity of the spermand/or egg for one another.

In 23 b a method is depicted in which the fallopian tubes are visualized9340 using MRI, CT, or ultrasound. HIFU 9350 is applied undervisualization with MRI or ultrasound. As the fallopian tubes are heated,the collagen in the wall is heated until the walls of the fallopian tubeclose off. At this point the patient is sterilized 9360. During thetreating time, it may be required to determine how effective the heatingis progressing. If additional heat is required, then additional HIFU maybe added to the fallopian tubes until there is closure of the tube andthe patient is sterilized 9360.

FIG. 24 depicts an algorithm to assess the effect of the neuralmodulation procedure on the autonomic nervous system. After a procedureis performed on the renal nerves, assessment of the autonomic responseis performed by, for example, simulating the autonomic nervous system inone or more places.

1-19. (canceled)
 20. A system to inhibit a function of a nerve travelingadjacent to a renal artery, comprising: a detector external to a patientto determine a location of the renal artery in a patient; an ultrasoundcomponent to deliver therapeutic energy to the nerve; and a modelingalgorithm configured to control the ultrasound component to targetregions on at least two sides of the renal artery; wherein the modelingalgorithm is configured to: determine a direction and an energy level ofthe therapeutic energy using the location of the renal artery and aposition of the ultrasound component relative to the renal artery; andgenerate an output for operating the ultrasound component, based on thedetermined location of the renal artery and the position of theultrasound component relative to the renal artery, to create a lesion atthe nerve.
 21. The system of claim 20 wherein the modeling algorithm isconfigured to consider heat transfer due to convection from the artery.22. The system of claim 21 wherein the modeling algorithm is furtherconfigured to consider heat transfer due to conduction of heat intissues surrounding the artery.
 23. The system of claim 20, wherein amajor axis of the lesion is longitudinal along a length of the artery.24. The system of claim 20, wherein the lesion comprises acircumferential lesion that at least partially surrounds a lumen of theartery.
 25. The system of claim 24, wherein the circumferential lesioncomprises multiple lesions that collectively form the circumferentiallesion.
 26. The system of claim 20, further comprising a fiducial,locatable by the detector from outside the patient, the fiducialconfigured to be temporarily placed in the renal artery of the patient.27. The system of claim 20, wherein the modeling algorithm is furtherconfigured to repeat the act of determining the direction and the energylevel, and the act of generating the output, to create one or moreadditional lesions.
 28. The system of claim 27, wherein the lesion andthe one or more additional lesions are at different respective sides ofthe renal artery.
 29. The system of claim 28, wherein the lesion and theone or more additional lesions collectively form a circumferentiallesion around a lumen of the renal artery.
 30. A method of inhibiting afunction of a nerve traveling adjacent to a renal artery, comprising:placing a therapeutic ultrasound energy source external to a patient;calculating power and phase for the therapeutic energy source, whereinthe power and the phase are calculated in consideration of a position ofthe therapeutic ultrasound energy source and a position of the renalartery; delivering first therapeutic ultrasound energy from thetherapeutic energy source, through a skin of the patient, to a firstregion on a first side at a adventitial region of the artery; anddelivering second therapeutic ultrasound energy from the therapeuticenergy source, through the skin of the patient, to a second region on asecond side at the adventitial region of the artery.
 31. The method ofclaim 30, wherein: the position of the renal artery is in the renalartery; the method further comprises determining the position of theartery using a fiducial that is internal to the patient; and the act ofdelivering the first therapeutic energy is performed based on thedetermined position of the renal artery.
 32. The method of claim 31,wherein the fiducial is a catheter placed in the artery of the patient.33. The method of claim 30, wherein the act of calculating the power andthe phase considers heat transfer due to convection from the artery. 34.The method of claim 33, wherein the act of calculating the power and thephase further considers heat transfer due to conduction of heat intissues surrounding the artery.
 35. The method of claim 30, wherein thefirst therapeutic energy from the therapeutic ultrasound energy sourceis delivered in a distribution along a length of the artery.